chr9-137619031-GGCCGCCGCCGATGCCGAGGTGAGCAGCGGGGCCGGCGGGGGGCGGCGCGGGGGCGGCGGGCAGCGGCGGAGGCGGCGCGGGGGCGAAGAACCGGGCGGGGCGGCGGCAGGCGGCCGGCGGGCGGGCGGGGCCCCGGGTCCCCCCGCCGCCGCCGCCGCCGCT-G

Position:

• chr9-137619031-GGCCGCCGCCGATGCCGAGGTGAGCAGCGGGGCCGGCGGGGGGCGGCGCGGGGGCGGCGGGCAGCGGCGGAGGCGGCGCGGGGGCGAAGAACCGGGCGGGGCGGCGGCAGGCGGCCGGCGGGCGGGCGGGGCCCCGGGTCCCCCCGCCGCCGCCGCCGCCGCT-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_024757.5(EHMT1):​c.13_21+153del variant causes a splice donor, splice donor 5th base, coding sequence, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A2A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: EHMT1 NM_024757.5 splice_donor, splice_donor_5th_base, coding_sequence, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.67

Genes affected

EHMT1 (HGNC:24650): (euchromatic histone lysine methyltransferase 1) The protein encoded by this gene is a histone methyltransferase that methylates the lysine-9 position of histone H3. This action marks the genomic region packaged with these methylated histones for transcriptional repression. This protein may be involved in the silencing of MYC- and E2F-responsive genes and therefore could play a role in the G0/G1 cell cycle transition. Defects in this gene are a cause of chromosome 9q subtelomeric deletion syndrome (9q-syndrome, also known as Kleefstra syndrome). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.0112907365 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-137619031-GGCCGCCGCCGATGCCGAGGTGAGCAGCGGGGCCGGCGGGGGGCGGCGCGGGGGCGGCGGGCAGCGGCGGAGGCGGCGCGGGGGCGAAGAACCGGGCGGGGCGGCGGCAGGCGGCCGGCGGGCGGGCGGGGCCCCGGGTCCCCCCGCCGCCGCCGCCGCCGCT-G is Pathogenic according to our data. Variant chr9-137619031-GGCCGCCGCCGATGCCGAGGTGAGCAGCGGGGCCGGCGGGGGGCGGCGCGGGGGCGGCGGGCAGCGGCGGAGGCGGCGCGGGGGCGAAGAACCGGGCGGGGCGGCGGCAGGCGGCCGGCGGGCGGGCGGGGCCCCGGGTCCCCCCGCCGCCGCCGCCGCCGCT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 573983.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EHMT1	NM_024757.5	c.13_21+153del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	1/27	ENST00000460843.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EHMT1	ENST00000460843.6	c.13_21+153del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	1/27	5	NM_024757.5

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Kleefstra syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 05, 2019

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Loss-of-function variants in EHMT1 are known to be pathogenic (PMID: 16826528, 19264732). This variant has not been reported in the literature in individuals with EHMT1-related disease. This variant is a deletion of the genomic region encompassing part of exon 1 (c.13_21+153del) of the EHMT1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1564509503; hg19: chr9-140513483;